Rheumatoid arthritis (R.A.) is a chronic disease characterized, primarily, by inflammation of the lining, also referred to as synovium, of the joints. Rheumatoid arthritis can lead to long-term joint damage with resulting chronic pain, loss of function and disability. Rheumatoid arthritis affects an estimated 1 to 2% of the world's population. As a matter of definition, rheumatoid arthritis is considered to be a chronic, symmetric polyarthritis (i.e., an arthritis involving more than 5 separate joints). Distinguishing characteristics include a positive blood test for rheumatoid factors in most patients, additional laboratory evidence of inflammation, lumps under the skin near bones or joints, known as “rheumatoid nodules,” specific joint involvement, and proliferative joint destruction. Despite these characteristics, diagnosis of rheumatoid arthritis is not always obvious and typically requires a medical history, a physical exam, lab tests, and imaging of joints or other areas known to be afflicted by the disease.
Radiographic images, such as x-ray images, provide a valuable baseline for comparing images taken at different points in time and are the mainstay of diagnosis for rheumatoid arthritis. For example, x-ray images show the swelling of the soft tissues and the loss of bone density around the affected joints that are the result of reduced activity and inflammation. As the disease progresses, x-ray images can show small holes or erosions near the ends of bones and narrowing of the joint space due to loss of cartilage. Doctors used to wait until the appearance of erosion before beginning aggressive treatment of the disease. However, now it is widely believed that it is better to treat rheumatoid arthritis aggressively before the development of erosions.
Methods and systems that rely on Magnetic Resonance Imaging (MRI) can detect a sign of early inflammation before it becomes visible on an x-ray image, and are particularly good at pinpointing synovitis. They provide greater sensitivity for bone erosions than radiography does, especially in the early phases of rheumatoid arthritis when radiography is relatively uninformative. This, along with the ability to detect pre-erosive features, such as synovitis and bone edema, allows MRI-based methods and systems to help identify patients with the aggressive phenotype of rheumatoid arthritis very early in the course of the disease. The MRI-based systems and methods can also be used to monitor disease progression and treatment response in clinical trials with greater statistical power than the radiography can offer.
Accordingly, as the introduction of structure-modifying therapy into mainstream clinical practice drives the demand for sensitivity and precision in predicting and monitoring erosive damage in early rheumatoid arthritis beyond the technical limits of conventional radiography, MRI-based systems and methods and specialized molecular markers have become increasingly attractive alternatives for evaluating therapeutic efficacy in clinical trials as well as in clinical practice. The cost associated with the MRI-based systems and methods, however, is proving to be prohibitive for routine clinical use. Thus, for the moment, analysis using radiography remains the primary image-based diagnostic tool.
One known approach for detection and tracking of rheumatoid arthritis is to determine scores or levels indicative of the severity and/or the progression of the disease. Existing systems for providing scores based on the severity of the disease and/or the extent to which the disease has progressed are divided into two groups: they are global and detailed scoring systems. Global scoring systems assign one score to an entire joint, taking into account all the abnormalities seen, whereas detailed systems assign scores on at least two separate variables for each joint evaluated.
The most widely used detailed scoring system is the Modified Sharp Scoring System and its variations, which are described in detail by Van der Heijde et al. in The Lancet, 1989; i: pp. 1036-38 and by Genant et al. in Arthritis Rheum., 1998; 41: pp. 1583-90. The most widely used global scoring system is the Modified Larsen Scoring Systems and its variations, which are described in detail by Rau et al. in The Journal of Rheumatology, 1995; 22: pp. 1976-82 and by Scott et al. in British Journal of Rheumatology, 1995; pp. 34:56.
The smallest detectable difference (SDD) of the Modified Sharp Scoring System, for example, is found to be 5.0 units out of a score that ranges between 0 and 488, and its mean sensitivity to changes at the threshold of the SDD for joint space width and erosions is 87% with a corresponding specificity of 83%, whereas when only erosions are considered, the sensitivity is 40-52% with a corresponding specificity of 92-100%, as presented by Bruynesteyn et al. in Arthritis & Rheum., 2002; 46(4): 913-920. It is desired that an automated method would provide a SDD that is no worse than 5.0 units, and preferably less than 3.0 units.
The Modified Sharp Scoring System also has an intra-rater reliability of intra-class correlation coefficients (ICC) that is equal to 0.96 for prevalence and an inter-rater reliability of ICC that ranges between 0.83 and 0.86 for progression, as presented by Boini et al. in Annals of the Rheumatic Diseases, 2001; 60: 817-827. It is desired that an automated method would provide corresponding intra-rater liability and inter-rater liability of ICC values that are no worse than what may be obtained manually, and preferably larger than 0.97 and 0.90, respectively.
The time needed to score radiographs of hands and feet with the Modified Sharp Scoring System ranges from 11.1 minutes to 20.5 minutes according to Van der Heijde et al. in Rheumatology, 1999; 38: 1213-20. Such magnitude of time delay is one drawback of scoring using the Modified Sharp Scoring System. It is desired that an automated method would preferably score a joint in less than 5 minutes.
Another approach for detection and tracking of rheumatoid arthritis was suggested by Langs et al. in Scandinavian Conference on Image Analysis 2003, Lecture Notes in Computer Science 2749, pp. 454-461, 2003 and Academic Radiology 2007, 14:1179-88. This particular approach uses an Active Shape Model (ASM), which is a type of statistical template, to identify the boundary of bones, such as finger bones. It then uses the identified boundary to draw around or annotate the boundary of erosions. It builds a statistical model from images of joints or bones free of the disease in order to find the bone contours, but then it uses the statistical model to annotate the erosions by driving a non-statistical model into the crenulations of the contour.
Several issues in developing and selecting a desired method or system for providing disease progression scores should be considered. Reader disagreement and inter- and intra-observer variations are important issues, though they can often be minimized by a sufficient training period to ensure familiarity with a particular scoring system or method. These problems are compounded by the need to assign a discrete number or score to a continuum of damage. Questions about the sensitivity of scoring systems or methods in detecting change over time have also been raised.
A recent report by an international panel of experts found that with the Modified Sharp Scoring systems and methods, the smallest detectable difference, which is 5.0 units, corresponded closely with the minimal clinically important difference (MCID), which is defined as radiographic progression for which a rheumatologist would consider changing or modifying the treatment. In contrast, the smallest detectable difference by the Modified Larsen systems and methods was found to be too insensitive to use as the threshold for clinically relevant change.
As a result, changes that occur to patients in the early phases of rheumatoid arthritis and to patients with more progressed rheumatoid arthritis as well as high disease activity in some cases often go undetected. The ability of scoring systems and methods to assess radiological sign of healing caused either by medical intervention or other means may also be an issue. Healing phenomena can be seen in about 6% of joints; this figure may be increased by the new disease-modifying anti-rheumatic drugs (DMARDs). Accordingly, radiographic scoring systems and methods used in clinical trials should be able to take the possibility of healing into account.
Therefore, there is a need to measure joint destruction as indicated by one or more of the presence of erosions and/or cysts, joint space narrowing, subluxation and other radiographic signs of joint degradation, or signs of healing, in the joints in a way that allows these measurements to be compared at various time points in a longitudinal study for individual patients.
A software system for building and using a statistical template was first developed between 1999 and 2001 by Gareth Edwards, Kevin Walker, and Alan Brett at Image Metrics Limited. The first version of the software system to demonstrate the capability of creating templates using samples of hand radiographs was built in February 2006.